N-glycosido benzimidazoles and process for preparation



Patented Aug. 5, 1952 N-GLYCOSIDO BENZIMIDAZOLES AND PROCESS FOR PREPARATION Dorothea Heyl Hoffman, Rahway, N. J assignor to Merck & 00., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Application August 2, 1950, Serial No. 177,336

This invention relates to an improved process for preparing benzimidazole, and more particularly to a method of obtaining the a-isomers of glycosidobenzimidazoles.

Certain of the a-glycosidobenzimidazoles are important since they have been found to promote the growth of animals when incorporated in the animal diet. For example, l-w-ribofuranosido 5,6 dimethylbenzimidazole, hereinafter also called a-ribazole, promotes the growth of certain animals when incorporated in the diet. Therefore, this substance is valuable for incorporation-in foodstuffs as a source of the necessary growth-promoting factor.

The synthesis of a-glycosidobenzimidazoles has previously been accomplished by imino-ether ring closure of the appropriate N-glycosido derivative which is described in the copending application, Serial No. 124,236, filed October 28, 1949. It has also been prepared by the reaction of a silver salt of 5,G-dimethylbenzimidazole and the appropriate haloacetosugar derivative. However, both of these processes possess an inherent disadvantage in that they result in the formation of significant amounts of the ii-isomer, which is difficult to separate from the desired a-isomer. Accordingly, a process which would yield essentially only the a-lSOIIlGI in good yields is extremely desirable. V

This invention is concerned with a method of preparing 1-glycosidobenzimidazoles. It is one object of the present invention to provide an improved process for obtaining these glycosidobenzimidazoles. It is a further object to provide a method whereby these a-glycosidobenzimidazoles can be readily prepared. Other objects will be apparent from the detailed description of the invention hereinafter provided.

According to the present invention found that l-glycosidobenzimidazoles are conveniently prepared by reacting the corresponding N-glycosido-1,2-phenylenediamines with carbon disulfide and barium hydroxide to produce the intermediate product, l-glycosido-Z-mercaptobenzimida-zole, and, intimately contacting this mercapto intermediate with Raney nickel to obtain the corresponding benzimidazole. The term glycosido as employed herein will be understood to include both unsubstituted, glycosido compounds as well as glycosido compounds substituted with groups that are readily removed by hydrolysis to obtain the free glycosido compound. Thus, in some cases we prefer to use a glycosido derivative having a hydrolysable group such as the trityl group on the primary hydroxy group.

it is now 14 Claims. (Cl..260 211.5)

Alternatively, the glycosido compound may be acylated, or substituted with acyl groups and a trityl group, which can be readily removed? by hydrolysis. These variations of my process will be readily apparent to those skilled in the art.

The reactions involved in the process of my invention may be illustratedasfollows:

i fon),

LSH l Raney nickel \N%CH V wherein R. represents a glycosido group, or a sub-* stituted glycosido group containing hydrolysable groups. Further, the benzene ring may be substituted by other groups such as alkyl, and the like.

The first step of my process is conveniently efiected by intimately contacting the 'N-gl'ycosidophenylenediamine with carbon disulfide and barium hydroxide and permitting the reaction to continue to completion. The time required for completion of'the reaction will vary depending upon the starting material used and the temperature, but generally I'find a minimum of'about sixhours is required. Sometimes I find it desirable to allow the mixture to react for 48 hours in order to obtain maximum yields. The temperature for carrying out the reaction may b varied depending upon the particular compound being treated In general, I find that temperatures ranging from about 15to 50 C.-'are satisfactory and that'a maximum yield is obtained at about 25 C. under optimum conditions. 1 find that it is preferable tocarryout the reaction in an inert solvent medium such as benzene, toluene, xylene, and the like.

The intermediate mercaptobenzimidazole is recovered from the reaction mixture by conventional chemical operations. In mo'st cases. I

find that it is conveniently recovered by removing the volatile constituents of the reaction mixture under reduced pressure, adding water to the resulting residue, acidifying the solution so obtained with an inorganic acid such as sulfuric acid, and extracting. the mercapto compound with a; suitable immiscible solvent as, for example chloroform. The desired intermediate is then recovered by evaporating the solvent solution to dryness.

The second step of my process: is. effected by dissolving the mercaptobenzimidazole compound in a suitable solvent such as: butyl alcohol, add,- ing Raney nickel thereto, and refluxing the. resulting mixture. After completion of the reaction, the suspended catalyst is removed by filtration and the benzimidazole recovered by evaporating the solvent.

When a compound having a substituted'glyco sido group is utilized as the starting material, thecorresnondingsubstituted". benzimitazole is obtainedbyimy process. If desired, the. free glycosl'do compound is readily obtained by acid hydrolysis.v For example, such, compounds.- are readily; hydrolyzed: by refluxing the substituted glycosidobenzimidazole with. an aqueous-alcoholic solution of hydrochloric acid.

In accordance with a further embodiment of this invention, I have found that this present method of effecting ring closure is particularly valuable for the preparation of lN-glycosido-5,6- dimethylbenzimidazoles. As indicated previously, this improved procedure is a valuable method for obtaining the a-isomeric form of 1-D ribofuranosido-5,6- dimethylbenzimidazole. Thus, contrary to the prior art processes wherein both the aand p-forms are obtained, only the a-isomer is obtained by the method of the present invention. It is indeed, surprising and unexpected to find that the process of the present invention produces essentially only the a-form and not the mixture of the a-fi-isomers. The present invention is therefore particularly valuable in that it provides a means of preparing a-IibaZOIB which is of nutritional importance.

In preparing a-ribazole by my new process We utilize the glycosido compound of the formula:

I CH: NH:

wherein R. is hydrogen or acyl, as the starting material. This compound, 2-amino-4,5-dimethyl---trityl-D-ribofuranosidoaniline is obtained by the condensation of 5-trityl-D-ribose and. 2- nitro-4,5-dimethyl-aniline, and. the subsequent hydrogenation of the 2-nitro-4,5-dimethyl-N- (5-trityl-D-ribofuranosido)aniline so obtained. This process is described in the copending application of Holly, Shunk, Cahill and Folkers, Serial No. 124,236, filed October 28, 1949. If desired, the corresponding acyl derivative is readily obtained by treating this product with an acyl anhydride such as acetic anhydride, propionic anhydride, and the like. I

Inaccordance with my present process, this compound, or the acylated derivative thereof, is converted to the corresponding mercaptobenzimidazole compounds by treatment with carbon disulfide and barium hydroxide. The mercapto compound is then reacted with Raney nickel to produce the corresponding glycosidobenzimidazole which on treatment with an aqueous-alcoholic solution of hydrochloric acid results in the hydrolysis of the trityl and acyl substituents of the glycosido group.

Similarly, the valuable compound, l-L-arabinosido-5,6-dimethylbenzimidazole is obtained utilizing 2-nitro-4,5-dimethyl-2,3,4.'-triacetyl- L-arabinopyranosidoaniline as the starting material.

The following examples are presented to illustrate, specific. embodiments of my invention.

Example 1 Twelve parts of 5-trityl-D-ribose prepared by the method of Bredereck, Kothnig and Berger, described in Berichte 73, 960 (1940) and 7.8 parts of 2-nitro-4,5'-dimethylaniline prepared in accordance with the method of Noelting, Braun and Thermar, Berichte 34, 2242 (1901) were dissolved in about 200 parts of benzene which had been dried by distillation. To this mixture was added 1 part of glacial acetic acid. The mixture was then refluxed for 2 hours, and the water that was formed in the reaction was taken off continuously. The solution was cooled in an ice bath. A- crystalline product was separated by filtration. The filtrate was concentrated in vacuo. The residue was treated with ethanol (213A) and allowed to stand in the cold room overnight and more crystalline material separated and was filtered oil. The filtrate was concentrated in vacuo to dryness. It was dissolved in a small volume of benzene and was chromatographed over 400 parts of acid-washed alumina. The column was eluted with benzene, then with ethanol giving 2-nitro-4,5-dimethyl-5'-trityl-D- ribofuranosidoaniline as a glass.

The 2 nitro 4,5-dimethyl-5 trityl-D-rlbofuranosidoaniline fraction eluted with ethanol was dissolved in about parts of pyridine and the solution was cooled to 0 C. Fifty parts of acetic anhydride were then added to the cold solution. It was then placed in the cold room overnight. Thenext day the solution was cooled to 0 3. in an ice-salt bathand then 75 parts of ethanol were added. The solution was concentrated invacuo to dryness. The residue was dissolved inethanol and allowed to stand in a cold room for five days. A mixture of oil and crystals separated. This mixture was taken up in ethanol and concentrated in vacuo again. The residue was taken up in benzene-petroleum ether solution (1-1) and chromatographed over 250 parts of alumina. Elution with benzene-petroleum ether (1-1) gave 2-nitro-4,5-dimethyl-2',3-dia;:etyl-5'-trityl D ribofuranosidoaniline as a g ass.

Five grams of 2-nitro-4,5-dimethyl-2',3'-diacetyl 5' trityl-D-ribofuranosidoaniline (prepared as described hereinabove and in Serial No. 124,236, filed October 28, 1949') dissolved in 100 cc. of benzene was reduced'to 2-a1nino-4,5-dimethyl-2',3-diacetyl-5 trityl D ribofurano sidoaniline by shaking with 1.5 g. of palladium Darco catalyst under a pressure of 2-3 lbs. of hydrogen; After removal of the catalyst and solvent, the syrupy amine, dissolved in 50 cc. of dry benzene, was stirred for two days with 20 cc. of carbon disulfide and 2.52 g. of barium hydroxide. The residue, after removal of the volatile material, was partitioned between chloroform and dilute sulfuric acid. The sulfuric acid fraction was extracted three times with chloroform, and the combined chloroform extracts washed three times with water. The chloroform solution, having been. dried over sodium sulfate, was concensulfhydryl-'5,6-dimethylbenzimidazole, was dissolved in 200cc. of butyl alcohol. The solution was. refluxed for three hours with one tablespoon fulof Raney nickel. The butyl alcohol was dis.-

tilled under reduced pressure and. the residue refluxed for two hours with a mixture of .15 cc.

of ethyl alcohol and 40 cc. of .617 .N hydrochloric acid. The resulting solution wasconcentrated to half its original volume, then extracted three times with chloroform; The aqueous solution,

cooled in an ice bath and made alkaline with sodium hydroxide, was extracted 'four times with chloroform. The almost colorless aqueous layer was cooled; reacidified with hydrochloric acid,

decolorized-with a. little Darco, and concentrated to remove the chloroform. Addition of aqueous picric acid brought down 0.43 g. of a-ribazole p1crate.

'The identity of the .picrate .so obtained was established-by a comparison with an authentic sample of 'a-ribazole picrate. The melting points of the picrate prepared by .thisexample, an authentic sample of a-ribazole, and a mixture of the two as determined simultaneously in capillaries were as follows: a-ribazole picrateprepared by processof example 200-202 0., authentic sample of a-ribazole picrate 206-207" (3., mixture. of two products ZOO-292 C. In addition, it was found '193'C. These melting pointswere determined simultaneously in capillaries.

Example 2 When the same experiment asdescribed in Extratedtto dryness and the; residue, consisting of *2";3"-1diacetal-R-trityl l D #ribofuranosidO-Q- ample l was carried out on the non-acetylated scribed in the preceding example.

Example 3 2 -nitro-4,5-dimethyl-2 ,3 ,4 -triacetyl-L-arabinopyranosidoaniline (2.1 g.) (prepared starting with L-arabinose and 2-nitro-4,5-dimethylaniline and utilizing the same procedure as that employed for preparing 2-nitro-4,5-dimethyl-2',3- diacetyl-5-trityl-D-ribofuranosidoaniline as described in Example 1 hereinabove and in Serial No. 124,236, filed October 28, 1949) was reduced in benzene solution with a palladium-D-arco cata lyst. After removal of the benzene under reduced pressure, the syrupy 2-amino-4.-,5-dimethyl-2,3- 4triacetyl-L--arabinopyranosidoaniline was further dried by addition and distillation of more benzene. The residue, dissolved in 50 cc. of dry benzene was treated with 10 cc. of carbon disulfide and 1.58 g. of finely ground barium hydroxide, and stirred at room temperature for two and one half days. The mixture was concentrated to dryness under reduced pressure, cc. of water added, the resulting mixture cooled in ice, and 6 N sulfuric acid added until the pH was 2. Hydrogen sulfide was removed by a current of air.

2-nitro-4,5-dimethyl-5-trityl-Dribo I The aqueous solution was extracted three times with chloroform, the suspended barium sulfate being removed by filtration. The combined chloroform extracts were washed with water, dried over sodium sulfate, filtered and concentrated to dryness under reduced'pressure. The remaining oil, consisting of 2 ,324-triacetyl-1-L-arabinopyran-osido-2-sulfhydryl-5,6 dimethylbenzimidazole, was dissolved in 200 cc'tof butyl alcohol and was refluxed with 91g. of Raney' nickel for three hours. .After removal ofthe nickel by filtration and the butylalcohol by distillation under reduced pressure, the residue was refluxed with a mixture of .15 cc. of alcohol and 40 cc. of 0.67 N hydrochloric :acid for two hours. The alcohol was re moved and the resulting aqueous solution extracted several times with chloroform; The

aqueous solution, cooledin ice, was made alkaline with 6 N- NaOH. The resulting mixture'was also extracted with chloroform, filtered, concentrated to about half the original volume, and treated with saturated aqueous picric acid. The picrate obtained had a M. P. of 209-'210 and was identical with a previously prepared sample of l-L-ara- -binosido-5,6-dimethylbenzimidazole. -wasabout 0.61 g.

The yield "Various changes and modifications may be made in carrying-out the present invention without departingfrom the spirit and scope thereof. Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of my invention.

l. The process for preparing a l-glycosidobenzimidazole which comprises reacting'an N-glycosideeorthophenylenediamine with carbon disulfide and barium hydroxide, recovering the corresponding I 1-glycosido-2-mercaptcbenzimidazole from the resulting reaction product, and reacting said glycosido mercaptobenzimidazole with Raney .riickeL- Y I '2."The process for preparing a 1-g lycos cido- -benzimidazole which comprises reacting an N- glycosido-orthophenylenediamine with carbon disulfide andbarium hydroxide; recovering the corresponding l-glycosido-2-mercaptobenzimidazole from the resulting reaction product, reacting said glycosido mercaptobenzimidazole with Raney nickel and recovering said gylco'sidobenzimidazole.

3; The process for preparing a l-glycosido-5,6- dimethylbenzimidazole which comprises reacting a 2-amino-4,5 dimethylglycosidoaniline with carbon disulfide and barium hydroxide, recovering the corresponding 1-glycosido-2-mercapto- 5,6-dimethylbenzimidazole from the resulting reaction product, and reacting said glycosido mercaptobenzimidazole with Raney nickel.

4. The process for preparing a 1-glyccsido-5,6- dimethylbenzimidazole which comprises reacting a 2-amino 4,5 dimethylglycosidoaniline with carbon disulfide and barium hydroxide, recovering the corresponding 1-glyeosido-2-mercapto- 5,6-dimethylbenzimidazole from the resulting reaction product, reacting said glycosido mercaptobenzimidazole with Raney nickel, and recovering said glycosido-5,6-dimethylbenzimidazole from 7 prises reacting .2 amino-4,5 dimethylglycosidoaniline with carbon disulflde and barium hydroxide.

7. The process for preparing l-a-ribofuranoside-5,6dimethylbenzimidazole which comprises reacting carbon disulfide and barium hydroxide with a compoundselected from the group which consists of 2-amino'-4,5-dimethyl-5'-trityl- D-ribofuranosidoaniline and 2,3-diacyl derivatives thereof, recovering the resulting. l-D-ribofuranosido-2-mercapto -5,6- dimethylbenz'imidazole compound from said reaction product, treating said l-D-ribofuranosido 2 mercapto- 5,6-dimethylbenzimidazole compound with Raney nickel to convert the 2-mercapto-substituent to hydrogen, and subjecting the l-D-riboiuranosido-5,6-dimethylbenzimidazole compound thus formed to acid hydrolysis.

8. The process for preparing l-a-ribofuranoside-5,6-dimethyl-benzimidazole which comprises reacting 2-amino-4,5-dimethyl-'2,3'-diacetyl-5'- trityl-D-ribofuranosidoaniline with carbon disulfide and barium hydroxide, recovering the corresponding 2',3- diacetyl -5'- trityl 1 D -'rib0- iuranosido-2-sulfhydryi-5,G-dimethyl-benzimidazole from the reaction product, treating said product with Raney nickel to obtain the. corresponding 2,3-diacetyl5'-trityl-1-D-ribofuranosido-5,6-dimethylbenzimidazole, and subjecting said benzimidazole to acid hydrolysis.

9. The process for preparing l-a-ribofuranosido-5,6-dimethylbenzimidazo1e which comprises reacting 2-amino-4,5-dimethyl-2',3-diacetyl-5'- trityl-D-ribofuranosidoaniline with carbon disulflde and barium hydroxide, recovering the corresponding 2',3-diacetyl-5'-trityl-1- D ribofuranosido -2-sulfhydryl5,6-dimethylbenzimidazole, treating said product with Raney nickel to obtain the corresponding 2',3-diacetyl-5'-trityll-D-ribofuranosido -5,6- dimethylbenzimidazole, hydrolyzing said benzimidazole by heating with hydrochloric acid in an aqueous-alcohol medium, and recovering 1-a-ribofuranosido-5,6-dimethylbenzimidazole as the picric acid salt from said bydrolysis solution.

10. The process of preparing l-L-arabinosido- '5,6-dimethylbenzimidazole which comprises reacting carbon disulfide and barium hydroxide with 2 amino 4,5 dimethyl-L-arabinopyranosidoaniline, recovering the l-L-arabinopyranosido -2- sulphydryl -5,6- dimethyl benzimidazole from the reaction product, and treating said product with Raney nickel to obtain I-L-arabinosido 5,6-dimethylbenzimidazole.

11. The process for preparing l-L-arabinosido- 5,6-dimethylbenzimidazole which comprises reacting 2-amino -4,5- dimethyl-2',3',4'-triacyl-L- arabinopyranosidoaniline with carbon disuli'ide and barium hydroxide, recovering 2,3,4'-triacyl -1-L- arabinopyranosido -2- sulphydryl -5,6- dimethylbenzimidazole from the reaction product, treating said product with Raney nickel to obtain 2',3',4'-triacyl 1 L arabinosido 5,6 dimethylbenzimidazole, and subjecting said product to acid hydrolysis.

12. The process for preparing ,l-L-arabinosido-5,6-dimethylbenzimidazole which comprises reacting 2-amino-4,5-dimethyl-2,3,4'-triacetyl- L arabinopyranosidoaniline with carbon disulfide and barium hydroxide, recovering 2',3',4'- triacetyl -1-L- arabinopyranosido -2- sulphydryl- 5,6-dimethylbenzimidazole from the reaction product, treating said product with Raney nickel to obtain 2,3,4-triacetyl-1-L-arabinosido-5,6- dimethylbenzimidazole, and subjecting said product to acid hydrolysis.

13. 2',3-diacetyl-5'-trityl-l-D-ribofuranosido- 2-sulphydryl-5,6-dimethy1benzimidazole.

14. 2,3',4'-triacetyl -1-L-arabinopyranosido-2- sulphydryl-5,6-dimethylbenzimidazole.

DOROTHEA HEYL HOFFMAN.

REFERENCES CITED The following references are of record in the file of this patent:

Pigman: Carbohydrate Chemistry, 1948, pages 378 to 381.

Karrer: Helv. Chim. Acta 18 (1935), pp. 70, 75, 77, 1438, 1439, 5 pages.

Honeyman: J. C. S., 1950, pages 967-971.

Beilstein, 4th ed., v. 24, page 119. 

1. THE PROCESS FOR PREPARING A 1-GLYCOSIDOBENZIMIDAZOLE WHICH COMPRISES REACTING AN N-GLYCOSIDO-ORTHOPHENYLENEDIAMINE WITH CARBON DISULFIDE AND BARIUM HYDROXIDE, RECOVERING THE CORRESPONDING 1-GLYCOSIDO-2-MERCAPTOBENZIMIDAZOLE FROM THE RESULTING REACTION PRODUCT, AND REACTING SAID GLYCOSIDO MERCAPTOBENZIMIDAZOLE WITH RANEY NICKEL. 